1,4-benzothiepin-1,1-dioxide derivatives which are substituted with fluorine, method for producing the same, drugs containing said compounds and use thereof

ABSTRACT

This invention relates to Novel 1,4-benzothiepin-1,1-dioxide derivatives which are substituted with fluorine, method for producing the same, drugs containing said compounds and use thereof.

Novel 1,4-benzothiepin-1,1-dioxide derivatives which are substitutedwith fluorine, method for producing the same, drugs containing saidcompounds and use thereof

The invention relates to fluorine-substituted 1,4-benzothiepin1,1-dioxide derivatives and the physiologically tolerated salts thereof.

1,4-Benzothiepin 1,1-dioxide derivatives of similar structure havepreviously been described (U.S. Pat. No. 5,994,391).

The invention was based on the object of providing further compoundswhich show a hypolipidemic effect.

The invention therefore relates to the compound of the formula I

in which the meanings are

-   X O, NH, CH₂ or a bond;-   R1 (C₁-C₆)-alkyl;-   R2, R2′, R3, R3′, R4, R4′, R5, R5′ independently of one another H,    F, Cl, Br, I, OH, —(CH₂)—OH, CH₂F, CHF₂, CF₃, NO₂, N₃, CN,    S(O)_(p)—R6, (C₁-C₆)-alkylene-S(O)_(p)—R6, COOH, COO(C₁-C₆)alkyl,    CONH₂, CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more    than one, or all hydrogen(s) in the alkyl radicals may be replaced    by fluorine;    -   phenyl, —(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl,        O—(CH₂)_(m)-phenyl, —(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl        ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF₃,        NO₂, ON, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH,        COOO—(C₁-C₆)-alkyl, CONH₂;-   where always at least one of the radicals R2, R2′, R3, R3′, R4, R4′    has the meaning of fluorine or R5, R5′ has the meaning of CH₂F, CHF₂    or CF₃;-   R6 H, OH, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂;-   n 2, 3, 4, 5, 6;-   m 1, 2, 3, 4, 5, 6;-   p 0, 1, 2;    and the pharmaceutically acceptable salts thereof.

Preference is given to compounds of the formula I in which the meaningsare

-   X NH;-   R1 (C₁-C₆)-alkyl;

R2, R2′, R3, R3′, R4, R4′, R5, R5′ independently of one another H, F,Cl, Br, I, OH, —(CH₂)—OH, CH₂F, CHF₂, CF₃, NO₂, N₃, CN, S(O)_(p)—R6,(C₁-C₆)-alkylene-S(O)_(p)—R6, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more than one, or allhydrogen(s) in the alkyl radicals may be replaced by fluorine;

-   -   phenyl, —(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl,        O—(CH₂)_(m)-phenyl, —(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl        ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF₃,        NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH,        COOO—(C₁-C₆)-alkyl, CONH₂;

-   where always at least one of the radicals R2, R2′, R3, R3′, R4, R4′    has the meaning of fluorine or R5, R5′ has the meaning of CH₂F, CHF₂    or CF₃;

-   R6 H, OH, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂;

-   n 2, 3, 4, 5, 6;

-   m 1, 2, 3, 4, 5, 6;

-   p 0, 1, 2;    and the pharmaceutically acceptable salts thereof.

Particular preference is given to compounds of the formula I in whichthe meanings are

-   X NH;-   R1 (C₁-C₆)-alkyl;-   R4 F;-   R4′ H, F;-   R2, R2′, R3, R3′, R5, R5′ independently of one another H, F, Cl, Br,    I, OH, —(CH₂)—OH, CH₂F, CHF₂, CF₃, NO₂, N₃, CN, S(O)_(p)—R6,    (C₁-C₆)-alkylene-S(O)_(p)—R6, COOH, COO(C₁-C₆)alkyl, CONH₂,    CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C6)-alkyl, where one, more    than one, or all hydrogen(s) in the alkyl radicals may be replaced    by fluorine;    -   phenyl, —(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl,        O—(CH₂)_(m)-phenyl, —(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl        ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF₃,        NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,        NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH,        COO—(C₁-C₆)-alkyl, CONH₂;-   R6 H, OH, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂;-   n 2, 3, 4, 5, 6;-   m 1, 2, 3, 4, 5, 6;-   p 0, 1, 2;    and the pharmaceutically acceptable salts thereof.

Preference is further given to compounds of the formula I in which one,two or three of the radicals R2, R2′, R3, R3′, R4, R4′, R5, R5′ have themeaning of OH.

Compounds of the formula I preferred in one embodiment are those inwhich the radical X is O.

Compounds of the formula I preferred in one embodiment are those inwhich the radical X is NH.

Compounds of the formula I preferred in one embodiment are those inwhich the radical X is CH₂.

Compounds of the formula I preferred in one embodiment are those inwhich the radical R1 is butyl.

Compounds of the formula I preferred in one embodiment are those inwhich the radical R1 is ethyl.

Compounds of the formula I preferred in one embodiment are those inwhich the radical at least one of the radicals R2, R2′, R3, R3′, R4,R4′, R5, R5′, R6 or R6′ is CH₂OH.

Compounds of the formula I preferred in one embodiment are those inwhich the radical at least one of the radicals R2, R2′, R3, R3′, R4,R4′, R5, R5′, R6 or R6′ is CH₂OSO₃H.

Compounds of the formula I preferred in one embodiment are those inwhich the radical at least one of the radicals R5 or R5′ is CH₂OH.

Compounds of the formula I preferred in one embodiment are those inwhich the radical at least one of the radicals R5 or R5′ is CH₂OSO₃H.

Compounds of the formula I preferred in one embodiment are those inwhich the structure of the formula I is as follows:

If radicals or substituents may occur more than once in the compounds ofthe formulae I, they may all independently of one another have thestated meaning and be identical or different.

The alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynyleneradicals in the radicals R1, R2, R2′, R3, R3′, R4, R4′, R5, R5′ and R6may be either straight-chain or branched.

The invention relates to compounds of the formula I in the form of theirtautomers, racemates, racemic mixtures, mixtures of stereoisomers, purestereoisomers, mixtures of diastereoisomers and pure diastereoisomers.The mixtures are separated for example by chromatographic means.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acidssuch as, for example, acetic acid, benzenesulfonic, benzoic, citric,ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acids. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts),trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine,lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for preparing or purifying pharmaceuticallyacceptable salts and/or for use in nontherapeutic, for example in vitroapplications.

The compounds of the invention may also exist in various polymorphousforms, e.g. as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds according to the invention belongwithin the framework of the invention and are a further aspect of theinvention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described hereinabove, and the saltsthereof as described herein.

An alkyl radical means a straight-chain or branched hydrocarbon chainhaving up to eight carbons, such as, for example, methyl, ethyl,isopropyl, tert-butyl, hexyl, heptyl, octyl. The alkyl radicals may besubstituted once or more than once as described above.

“Patient” means a warm blooded animal, such as for example rat, mice,dogs, cats, guinea pigs, and primates such as humans.

“Treat” or “treating” means to alleviate symptoms, eliminate thecausation of the symptoms either on a temporary or permanent basis, orslow the appearance of symptoms of the named disorder or condition.

“Therapeutically effective amount” means a quantity of the compoundwhich is effective in treating the named disorder or condition.

“Pharmaceutically acceptable carrier” is a non-toxic solvent,dispersant, excipient, adjuvant or other material which is mixed withthe active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

The compound(s) of the formula I can also be administered in combinationwith further active ingredients.

The amount of a compound of formula I necessary to achieve the desiredbiological effect depends on a number of factors, for example thespecific compound chosen, the intended use, the mode of administrationand the clinical condition of the patient. The daily dose is generallyin the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) perday and per kilogram of body weight, for example 3-10 mg/kg/day. Anintravenous dose may be for example in the range from 0.3 mg to 1.0mg/kg, which can suitably be administered as infusion of from 10 ng to100 ng per kilogram per minute. Suitable infusion solutions for thesepurposes may comprise for example from 0.1 ng to 10 mg, typically from 1ng to 10 mg, per milliliter. Single doses may comprise for example from1 mg to 10 g of the active ingredient. Thus, ampules for injections maycomprise for example from 1 mg to 100 mg, and single-dose formulationswhich can be administered orally, such as, for example, tablets orcapsules, may comprise for example from 1.0 to 1000 mg, typically from10 to 600 mg. For the therapy of the abovementioned conditions, thecompounds of formula I may be used as the compound itself, but they arepreferably in the form of a pharmaceutical composition with anacceptable carrier. The carrier must, of course, be acceptable in thesense that it is compatible with the other ingredients of thecomposition and is not harmful for the patient's health. The carrier maybe a solid or a liquid or both and is preferably formulated with thecompound as a single dose, for example as a tablet, which may containfrom 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, cachets, suckabletablets or tablets, each of which contains a defined amount of thecompound of formula I; as powders or granules; as solution or suspensionin an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single patches whichare suitable for long-term close contact with the patient's epidermis.Such patches suitably contain the active ingredient in an aqueoussolution which is buffered where appropriate, dissolved and/or dispersedin an adhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. Aparticular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

Further active ingredients suitable for combination products are: Allantidiabetics which are mentioned in the Rote Liste 2006, chapter 12;all weight-reducing agents/appetite suppressants which are mentioned inthe Rote Liste 2006, chapter 1; all lipid-lowering agents which arementioned in the Rote Liste 2006, chapter 58. They may be combined withthe compound of the invention of the formula I in particular for asynergistic improvement in the effect. The active ingredient combinationcan be administered either by separate administration of the activeingredients to the patient or in the form of combination products inwhich a plurality of active ingredients is present in a pharmaceuticalpreparation. Most of the active ingredients mentioned hereinafter aredisclosed in the USP Dictionary of USAN and International Drug Names, USPharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives such as, forexample, Lantus® (see www.lantus.com) or HMR 1964 or Levemir® (insulindetemir) or those described in WO2005005477 (Novo Nordisk), fast-actinginsulins (see U.S. Pat. No. 6,221,633), inhalable insulins such as, forexample, Exubera® or oral insulins such as, for example, IN-105 (Nobex)or Oral-lyn™ (Generex Biotechnology), GLP-1 derivatives such as, forexample, exenatide, liraglutide or those which have been disclosed in WO98/08871, WO2005027978, WO2006037811 or WO2006037810 of Novo NordiskA/S, in WO 01/04156 of Zealand or in WO 00/34331 of Beaufour-Ipsen,pramlintide acetate (Symlin; Amylin Pharmaceuticals), and orallyeffective hypoglycemic active ingredients.

The orally effective hypoglycemic active ingredients include preferably

-   sulfonylureas,-   biguanidines,-   meglitinides,-   oxadiazolidinediones,-   thiazolidinediones,-   glucosidase inhibitors,-   inhibitors of glycogen phosphorylase,-   glucagon antagonists,-   glucokinase activators,-   inhibitors of fructose-1,6-bisphosphatase,-   modulators of glucose transporter 4 (GLUT4),-   inhibitors of glutamine-fructose-6-phosphate amidotransferase    (GFAT),-   GLP-1 agonists, potassium channel openers such as, for example,    those which have been disclosed in WO 97/26265 and WO 99/03861 of    Novo Nordisk A/S, or those which are described in WO2006045799    (Solvay),-   inhibitors of dipeptidylpeptidase IV (DPP-IV),-   insulin sensitizers,-   inhibitors of liver enzymes involved in stimulating gluconeogenesis    and/or glycogenolysis,-   modulators of glucose uptake, of glucose transport and of glucose    reabsorption,-   inhibitors of 11β-HSD1,-   inhibitors of protein tyrosine phosphatase 1B (PTP1B),-   modulators of the sodium-dependent glucose transporter 1 or 2    (SGLT1, SGLT2),-   compounds which alter lipid metabolism such as antihyperlipidemic    active ingredients and antilipidemic active ingredients,-   compounds which reduce food intake,-   compounds which increase thermogenesis,-   PPAR and RXR modulators and-   active ingredients which act on the ATP-dependent potassium channel    of the beta cells.

In one embodiment of the invention, the compounds of the formula I isadministered in combination with an HMGCoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin or L-659699.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol absorption inhibitor suchas, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497,WO2005021495) or with compounds as described in WO2002066464 (KotobukiPharmaceutical Co. Ltd.), or WO2005044256 or WO2005062824 (Merck & Co.)or WO2005061451 and WO2005061452 (AstraZeneca AB), and WO2006017257(Phenomix) or WO2005033100 (Lipideon Biotechnology AG).

In one embodiment of the invention, the compound of the formula I isadministered in combination with Vytorin™, a fixed combination ofezetimibe and simvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fixed combination of ezetimibe withfenofibrate.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a fixed combination of fenofibrateand rosuvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with ISIS-301012, an antisenseoligonucleotide able to regulate the apolipoprotein B gene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR gamma agonist such as, forexample, rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483, CS-011(rivoglitazone).

In one embodiment of the invention, the compound of the formula I isadministered in combination with Competact™, a fixed combination ofpioglitazone hydrochloride with metformin hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with duetact™, a fixed combination ofpioglitazone hydrochloride with glimepiride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Avandamet®, a fixed combination ofrosiglitazone maleate with metformin hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR alpha agonist such as, forexample, GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR alpha/gamma agonist suchas, for example, naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042,AVE 8134, AVE 0847, or as described in PCT/US 00/11833, PCT/US 00/11490,DE10142734.4 or in J. P. Berger et al., TRENDS in PharmacologicalSciences 28(5), 244-251, 2005.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR delta agonist such as, forexample, GW-501516.

In one embodiment, the compound of the formula I is administered incombination with metaglidasen or with MBX-2044 or other partial PPARgamma agonists/antagonists.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an activator of AMP-activatedprotein kinase (AMPK) such as, for example, A-769662 or those compoundsdescribed in US 20050038068.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate such as, for example,fenofibrate, clofibrate or bezafibrate.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an MTP inhibitor such as, for example,implitapide, BMS-201038, R-103757 or those described in WO2005085226,WO2005121091, WO2006010423.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor such as, for example,torcetrapib or JTT-705 or those described in WO2006002342, WO2006010422,WO2006012093.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a bile acid absorption inhibitor (see,for example, U.S. Pat. Nos. 6,245,744, 6,221,897 or WO00/61568), suchas, for example, HMR 1741 or those as described in DE 10 2005 033099.1and DE 10 2005 033100.9.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorbent suchas, for example, cholestyramine or colesevelam.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), such as, for example, HMR1171, HMR1586 or those asdescribed in WO2005097738.

In one embodiment, the compound of the formula I is administered incombination with Omacor® (omega-3 fatty acids; highly concentrated ethylesters of eicosapentaenoic acid and of docosahexaenoic acid).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor such as, for example,avasimibe or SMP-797.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant such as, for example,OPC-14117, probucol, tocopherol, ascorbic acid, β-carotene or selenium.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin such as, for example, vitaminB6 or vitamin B12.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator such as,for example, ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ATP citrate lyase inhibitor such as,for example, SB-204990.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor suchas, for example, BMS-188494 or as described in WO2005077907.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein(a) antagonist such as,for example, gemcabene (CI-1027).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR109A (HM74A receptoragonist) such as, for example, nicotinic acid or extended release niacinin conjunction with MK-0524A or those compounds described inWO2006045565, WO2006045564, WO2006069242.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR116 as are describedfor example in WO2006067531, WO2006067532.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor such as, forexample, orlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In one embodiment, the compound of the formula I is administered incombination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glipizide or glimepiride.

In one embodiment, the compound of the formula I is administered incombination with a substance which enhances insulin secretion, such as,for example, KCP-265 (WO2003097064).

In one embodiment, the compound of the formula I is administered incombination with agonists of the glucose-dependent insulinotropicreceptor (GDIR) such as, for example, APD-668.

In one embodiment, the compound of the formula I is administered incombination with a biguanide such as, for example, metformin.

In yet another embodiment, the compound of the formula I is administeredin combination with a meglitinide such as, for example, repaglinide ornateglinide.

In one embodiment, the compound of the formula I is administered incombination with a thiazolidinedione such as, for example, troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compound of the formula I is administered incombination with an α-glucosidase inhibitor such as, for example,miglitol or acarbose.

In one embodiment, the compound of the formula I is administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compound of the formula I is administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen phosphorylase, such as, forexample, PSN-357 or FR-258900 or those as described in WO2003084922,WO2004007455, WO2005073229-31 or WO2005067932.

In one embodiment, the compound of the formula I is administered incombination with glucagon receptor antagonists such as, for example,A-770077, NNC-25-2504 or as described in WO2004100875 or WO2005065680.

In one embodiment, the compound of the formula I is administered incombination with activators of glucokinase, such as, for example,LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those as aredescribed for example in WO2004072031, WO2004072066, WO2005080360,WO2005044801, WO2006016194, WO2006058923.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of gluconeogenesis, such as, for example,FR-225654.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of fructose-1,6-bisphosphatase (FBPase),such as, for example, CS-917 (MB-06322) or MB-07803 or those describedin WO2006023515.

In one embodiment, the compound of the formula I is administered incombination with modulators of glucose transporter 4 (GLUT4), such as,for example, KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54(12), 835 (2004)).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of glutamine-fructose-6-phosphateamidotransferase (GFAT), as are described for example in WO2004101528.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of dipeptidylpeptidase IV (DPP-IV), such as,for example, vildagliptin (LAF-237), sitagliptin (MK-0431), saxagliptin(BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021,GRC-8200, GW-825964X, KRP-104, DP-893 or as are described inWO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312,WO2005/1012308, WO2006039325, WO2006058064, PCT/EP2005/007821,PCT/EP2005/008005, PCT/EP2005/008002, PCT/EP2005/008004,PCT/EP2005/008283, DE 10 2005 012874.2 or DE 10 2005 012873.4.

In one embodiment, the compound of the formula I is administered incombination with Januvia™, a fixed combination of sitagliptin phosphatewith metformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of 11-beta-hydroxysteroid dehydrogenase 1(11β-HSD1), such as, for example, BVT-2733, JNJ-25918646, INCB-13739 orthose as are described for example in WO200190090-94, WO200343999,WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310,WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208,WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251,WO2004056744, WO2004058730, WO2004065351, WO2004089367, WO2004089380,WO2004089470-71, WO2004089896, WO2005016877, WO2005097759, WO2006010546,WO2006012227, WO2006012173, WO2006017542, WO2006034804, WO2006040329,WO2006051662, WO2006048750, WO2006049952, WO2006048331, WO2006050908,WO2006024627, WO2006040329, WO2006066109.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of protein tyrosine phosphatase 1B (PTP1B),as are described for example in WO200119830-31, WO200117516,WO2004506446, WO2005012295, WO2005116003, PCT/EP2005/005311,PCT/EP2005/005321, PCT/EP2005/007151, PCT/EP2005/01294 or DE 10 2004060542.4.

In one embodiment, the compound of the formula I is administered incombination with modulators of the sodium-dependent glucose transporter1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727, T-1095, SGL-0010,AVE 2268 and SAR 7226 or as are described for example in WO2004007517,WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630,WO2005121161, WO2006018150, WO2006035796, WO2006062224, WO2006058597 orby A. L. Handlon in Expert Opin. Ther. Patents (2005) 15(11), 1531-1540.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR40.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119b as are described for example inWO2004041274.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119 as are described for example inWO2005061489 (PSN-632408).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of hormone-sensitive lipase (HSL) asdescribed for example in WO2005073199.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of acetyl-CoA carboxylase (ACC), such as,for example, those as described in WO199946262, WO200372197,WO2003072197, WO2005044814, WO2005108370, JP2006131559.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of phosphoenolpyruvate carboxykinase(PEPCK), such as, for example, those as described in WO2004074288.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen synthase kinase 3 beta (GSK-3beta), as described for example in US2005222220, WO2005085230,PCT/EP2005/005346, WO2003078403, WO2004022544, WO2003106410,WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836,WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727 orWO2004046117.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of protein kinase C beta (PKC beta), suchas, for example, ruboxistaurin.

In one embodiment, the compound of the formula I is administered incombination with an endothelin A receptor antagonist such as, forexample, avosentan (SPP-301).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of “I-kappaB kinase” (IKK inhibitors), asare described for example in WO2001000610, WO2001030774, WO2004022553 orWO2005097129.

In one embodiment, the compound of the formula I is administered incombination with modulators of the glucocorticoid receptor, as aredescribed for example in WO2005090336.

In a further embodiment, the compound of the formula I is administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9),554-558);

-   NPY antagonists such as, for example, naphthalene-1-sulfonic acid    {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide    hydrochloride (CGP 71683A);-   NPY-5 receptor antagonists such as L-152804, S-2367 or as are    described for example in WO2006001318;-   Peptide YY 3-36 (PYY3-36) or analogous compounds, such as, for    example, CJC-1682 (PYY3-36 conjugated with human serum albumin via    Cys34), CJC-1643 (derivative of PYY3-36 which conjugates in vivo to    serum albumin) or those as are described in WO2005080424;-   CB1R (cannabinoid receptor 1) antagonists (such as, for example,    rimonabant, SR147778 or those as are described for example in EP    0656354, WO 00/15609, WO 02/076949, WO2005080345, WO2005080328,    WO2005080343, WO2005075450, WO2005080357, WO200170700,    WO2003026647-48, WO200302776, WO2003040107, WO2003007887,    WO2003027069, US6,509,367, WO200132663, WO2003086288, WO2003087037,    WO2004048317, WO2004058145, WO2003084930, WO2003084943,    WO2004058744, WO2004013120, WO2004029204, WO2004035566,    WO2004058249, WO2004058255, WO2004058727, WO2004069838,    US20040214837, US20040214855, US20040214856, WO2004096209,    WO2004096763, WO2004096794, WO2005000809, WO2004099157,    US20040266845, WO2004110453, WO2004108728, WO2004000817,    WO2005000820, US20050009870, WO200500974, WO2004111033-34,    WO200411038-39, WO2005016286, WO2005007111, WO2005007628,    US20050054679, WO2005027837, WO2005028456, WO2005063761-62,    WO2005061509, WO2005077897, WO2006047516, WO2006060461,    WO2006067428, WO2006067443); MC4 agonists (e.g.    1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid    [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide;    (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,    CHIR-785, PT-141 or those that are described in WO2005060985,    WO2005009950, WO2004087159, WO2004078717, WO2004078716,    WO2004024720, US20050124652, WO2005051391, WO2004112793,    WOUS20050222014, US20050176728, US20050164914, US20050124636,    US20050130988, US20040167201, WO2004005324, WO2004037797,    WO2005042516, WO2005040109, WO2005030797, US20040224901,    WO200501921, WO200509184, WO2005000339, EP1460069, WO2005047253,    WO2005047251, EP1538159, WO2004072076, WO2004072077 or    WO2006021655-57;-   orexin receptor antagonists (e.g.    1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea    hydrochloride (SB-334867-A) or those as are described for example in    WO200196302, WO200185693, WO2004085403, WO2005075458 or    WO2006067224);-   histamine H3 receptor agonists (e.g.    3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one    oxalic acid salt (WO 00/63208) or those as are described in    WO200064884, WO2005082893);-   CRF antagonists (e.g.    [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine    (WO 00/66585));-   CRF BP antagonists (e.g. urocortin);-   urocortin agonists;-   agonists of the beta-3 adrenoceptor such as, for example,    1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol    hydrochloride (WO 01/83451); or Solabegron (GW-427353) or N-5984    (KRP-204) or those described in JP2006111553;-   MSH (melanocyte-stimulating hormone) agonists;-   MCH (melanin-concentrating hormone) receptor antagonists (such as,    for example, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296,    T-71, GW-803430 or compounds such as are described in WO2003/15769,    WO2005085200, WO2005019240, WO2004011438, WO2004012648,    WO2003015769, WO2004072025, WO2005070898, WO2005070925,    WO2004039780, WO2003033476, WO2002006245, WO2002089729,    WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680,    WO2006044293, WO2006044174);-   CCK-A agonists (such as, for example,    {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic    acid trifluoroacetic acid salt (WO 99/15525), SR-146131 (WO 0244150)    or SSR-125180 or those as are described in WO2005116034);-   serotonin reuptake inhibitors (e.g. dexfenfluramine);-   mixed sertoninergic and noradrenergic compounds (e.g. WO 00/71549);-   5-HT receptor agonists, e.g. 1-(3-ethylbenzofuran-7-yl)piperazine    oxalic acid salt (WO 01/09111);-   5-HT2C receptor agonists (such as, for example, lorcaserin    hydrochloride (APD-356), BVT-933 or those as are described in    WO200077010, WO20077001-02, WO2005019180, WO2003064423, WO200242304    or WO2005082859);-   5-HT6 receptor antagonists as are described for example in    WO2005058858;-   bombesin receptor agonists (BRS-3 agonists);-   galanin receptor antagonists;-   growth hormone (e.g. human growth hormone or AOD-9604);-   growth hormone-releasing compounds (tertiary butyl    6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate    (WO 01/85695));-   growth hormone secretagogue receptor antagonists (ghrelin    antagonists) such as, for example, A-778193 or those as are    described in WO2005030734;-   TRH agonists (see, for example, EP 0 462 884);-   uncoupling protein 2 or 3 modulators;-   leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew    C.;-   Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a    potential approach to the treatment of obesity. Drugs of the Future    (2001), 26(9), 873-881);-   DA agonists (bromocriptine or Doprexin);-   lipase/amylase inhibitors (for example WO 00/40569);-   inhibitors of diacylglycerol O-acyltransferases (DGATs) such as, for    example, BAY-74-4113 or as described for example in US2004/0224997,    WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492,    WO2005013907, WO2006004200, WO2006019020, WO2006064189;-   inhibitors of fatty acid synthase (FAS) such as, for example, C75 or    those as described in WO2004005277;-   oxyntomodulin;-   oleoyl-estrone-   or thyroid hormone receptor agonists such as, for example: KB-2115    or those as described in WO20058279, WO200172692, WO200194293,    WO2003084915, WO2004018421 or WO2005092316.

In one embodiment, the further active ingredient is vareniclinetartrate, a partial agonist of the alpha 4-beta 2 nicotinicacetylcholine receptor.

In one embodiment, the further active ingredient is trodusquemine.

In one embodiment, the further active ingredient is a modulator of theSIRT1 enzyme, a member of the human sirtuin enzyme family.

In one embodiment of the invention, the further active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the further active ingredient is dexamphetamine oramphetamine.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In one embodiment, the further active ingredient is mazindole orphentermine.

In one embodiment, the compound of the formula I is administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, Carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Hochst, 65926 Frankfurt/Main). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

It will be understood that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more further pharmacologically active substances willbe regarded as falling within the protection conferred by the presentinvention.

The examples detailed below serve to illustrate the invention without,however, restricting it.

TABLE 1 I

Ex. R1 R2, R2′ R3, R3′ R4, R4′ R5, R5′ X 1 Et OH, H OH, H F, H CH₂OH, HNH 2 Et OH, H OH, H F, H CH₂OSO₂OH, H NH 3 Et OH, H OH, H F, F CH₂OH, HNH 4 Et OH, H OH, H F, F CH₂OSO₂OH, H NH 5 Et OH, H OH, H F, H CH₂SO₂OH,H NH Et = ethyl

The activity of the compounds was assayed as follows:

Preparation and procedure for the in vitro IBAT inhibition assay:

1. Cloning of an Expression Vector for Human IBAT

The cDNA (complementary deoxyribonucleic acid) of human IBAT was clonedby standard methods of molecular biology as described for example inMolecular Cloning: A Laboratory Manual by Joseph Sambrook and DavidRussell, and introduced into the pcDNA1 vector from Invitrogen. Thesubsequent sequencing of the insert revealed complete identity withbases 599 to 1645 of the base sequence for human IBAT which wasdescribed by P. A. Dawson and is deposited in the Gen Bank sequencedatabase (GenBank Accession Number: U10417). Bases 599 to 1645correspond to the complete coding region of human IBAT.

2. Preparation of a Recombinant Cell Line with Constitutive Expressionof Human IBAT

The expression vector for human IBAT was introduced by stabletransfection into CHO (chinese hamster ovary) cells. To select singlecell clones, 400 μg/ml Geneticin was added to the cell culture medium(Ham's F12 medium supplemented with 10% fetal calf serum, 100 units/mlpenicillin, 100 units/ml streptomycin). The functionality of the singlecell clones resulting from the selection was assayed via their uptakeactivity for radiolabeled taurocholic acid ([³H]-TCA). The cell clonewith the highest uptake activity for [³H]-TCA, referred to hereinafteras CHO-hIBAT, was selected for the further assays and further culturedin the presence of 400 μg/ml Geneticin.

3. Measurement of the Inhibitory Effect of the Compound of the Inventionon the IBAT-Dependent Uptake of Taurocholic Acid into Cells

CHO-hIBAT cells were seeded in a concentration of 40 000 cells per wellin poly-D-lysine-coated 96-well plates in cell culture medium andcultured for 24 h. The cells were then washed once with sodium-freetransport assay buffer (140 mM choline chloride, 2 mM potassiumchloride, 1 mM magnesium chloride, 1 mM calcium chloride, 10 mMHEPES/Tris, pH 7.5) and subsequently incubated either with sodium-freetransport assay buffer as negative control or with sodium-containingtransport assay buffer (140 mM sodium chloride, 2 mM potassium chloride,1 mM magnesium chloride, 1 mM calcium chloride, 10 mM HEPES/Tris, pH7.5) as positive control at room temperature for 30 min. At the sametime, the assay wells were also incubated in the presence of thecompound to be investigated in varying concentration insodium-containing transport assay buffer at room temperature for 30 min.The test substances were appropriately diluted in transport assay buffer(40 μl/well) starting from a 10 mM stock solution in dimethyl sulfoxide.The assay was then started by adding 10 μl/well of a mixture ofradiolabeled taurocholic acid ([³H]-TCA) and unlabeled taurocholic acid.The final concentration of taurocholic acid in the assay was 10 μM.After an incubation time of 60 min at room temperature, the reaction wasstopped by adding 100 μl/well sodium-free transport assay buffer (4°C.), and each well was washed three times with sodium-free transportassay buffer. Finally, 100 μl of scintillation fluid were added to eachwell, and the radioactivity taken up into the cells was determined in aMicroBeta Scintillation Microplate Reader from Wallac.

The half-maximum inhibitory effect of the test compound (IC50 value,inhibitory concentration 50) was determined in the following way:

-   -   1. Determination of the value for 0% inhibition. This is the        measurement in the absence of substance, measured in        sodium-containing transport assay buffer.    -   2. Determination of the value for 100% inhibition. This is the        measurement in the absence of substance, measured in sodium-free        transport assay buffer.    -   3. Calculation of the percentage inhibitions of those        measurements carried out in the presence of various        concentrations of the compound to be investigated. It was then        possible to find therefrom the concentration of the compound        which reduces the uptake of taurocholic acid by 50% (IC50        value).

TABLE 2 Biological activity IC-50 (human Ex. IBAT) μM 1 0.0065 2 0.00393 0.0053 4 0.0036 5 0.0056

It can be inferred from the measured data that the compounds of theinvention of the formula I are very suitable for the treatment ofhyperlipidemia.

The use of the compounds of the formula I for the treatment orprevention of further diseases is likewise conceivable. Examples of suchdiseases are:

-   1. disorders of fatty acid metabolism and glucose utilization    disorders    -   disorders in which insulin resistance is involved-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.    -   Particular aspects in this connection are    -   hyperglycemia,    -   improvement in insulin resistance,    -   improvement in glucose tolerance,    -   protection of the pancreatic β cells    -   prevention of macro- and microvascular disorders-   3. Dyslipidemias and their sequelae such as, for example,    atherosclerosis, coronary heart disease, cerebrovascular disorders    etc, especially those (but not restricted thereto) which are    characterized by one or more of the following factors:    -   high plasma triglyceride concentrations, high postprandial        plasma triglyceride concentrations,    -   low HDL cholesterol concentration    -   low apoA lipoprotein concentrations    -   high LDL cholesterol concentrations    -   small dense LDL cholesterol particles    -   high apoB lipoprotein concentrations    -   desaturation index (e.g. ratio 18:1/18:0n-9, 16:1/16:0 n-7 or        18:1n-9+16:1n-7/16:0 fatty acids)-   4. Various other conditions which may be associated with the    metabolic syndrome or syndrome X, such as:    -   increased abdominal girth    -   dyslipidemia (e.g. hypertriglyceridemia and/or low HDL)    -   insulin resistance    -   hypercoagulability    -   hyperuricemia    -   microalbuminemia    -   thromboses, hypercoagulable and prothrombotic states (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy-   5. Hepatic disorders and conditions related thereto    -   fatty liver    -   hepatic steatosis    -   non-alcoholic hepatitis    -   non-alcoholic steatohepatitis (NASH)    -   alcoholic hepatitis    -   acute fatty liver    -   fatty liver of pregnancy    -   drug-induced hepatitis    -   iron overload disorders    -   hepatic fibrosis    -   hepatic cirrhosis    -   hepatoma    -   viral hepatitis-   6. Skin disorders and conditions and those associated with    polyunsaturated fatty acids    -   eczema    -   acne    -   psoriasis    -   keloid scar formation or prevention    -   other diseases related to mucous membrane fatty acid composition-   7. Primary hypertriglyceridemia or secondary hypertriglyceridemias    following    -   familial histiocytic reticulosis    -   lipoprotein lipase deficiency    -   hyperlipoproteinemias    -   apolipoprotein deficiency (e.g. apoCII or apoE deficiency)-   8. Diseases or conditions related to neoplastic cellular    proliferation    -   benign or malignant tumors    -   cancer    -   neoplasia    -   metastases    -   carcinogenesis-   9. Diseases or conditions related to neurological, psychiatric or    immune disorders or conditions-   10. Other diseases or conditions in which inflammatory reactions or    cell differentiation may for example be involved are:    -   atherosclerosis such as, for example (but not restricted        thereto), coronary sclerosis including angina pectoris or        myocardial infarction, stroke, ischemic stroke and transient        ischemic attack (TIA)    -   peripheral occlusive disease    -   vascular restenosis or reocclusion    -   chronic inflammatory bowel diseases such as, for example,        Crohn's disease and ulcerative colitis    -   pancreatitis    -   sinusitis    -   other inflammatory conditions    -   retinopathy, ischemic retinopathy    -   adipose cell tumors    -   lipomatous carcinomas such as, for example, liposarcomas    -   solid tumors and neoplasms such as, for example (but not        restricted thereto), carcinomas of the gastrointestinal tract,        of the liver, of the biliary tract and of the pancreas,        endocrine tumors, carcinomas of the lungs, of the kidneys and        the urinary tract, of the genital tract, prostate carcinomas etc    -   acute and chronic myeloproliferative disorders and lymphomas    -   angiogenesis    -   neurodegenerative disorders    -   Alzheimer's disease    -   multiple sclerosis    -   Parkinson's disease    -   erythemato-squamous dermatoses such as, for example, psoriasis    -   acne vulgaris    -   other skin disorders and dermatological conditions which are        modulated by PPAR    -   eczemas and neurodermatitis    -   dermatitis such as, for example, seborrheic dermatitis or        photodermatitis    -   keratitis and keratoses such as, for example, seborrheic        keratoses, senile keratoses, actinic keratosis, photo-induced        keratoses or keratosis follicularis    -   keloids and keloid prophylaxis    -   warts, including condylomata or condylomata acuminata    -   human papilloma viral (HPV) infections such as, for example,        venereal papillomata, viral warts such as, for example,        molluscum contagiosum, leukoplakia    -   papular dermatoses such as, for example, lichen planus    -   skin cancer such as, for example, basal-cell carcinomas,        melanomas or cutaneous T-cell lymphomas    -   localized benign epidermal tumors such as, for example,        keratoderma, epidermal naevi    -   chilblains    -   high blood pressure    -   syndrome X    -   polycystic ovary syndrome (PCOS)    -   asthma    -   cystic fibrosis    -   osteoarthritis    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   vasculitis    -   wasting (cachexia)    -   gout    -   ischemia/reperfusion syndrome    -   acute respiratory distress syndrome (ARDS)    -   viral diseases and infections    -   lypodystrophy and lipodystrophic conditions, also for treating        adverse drug effects (e.g. after taking medicaments for treating        HIV or tumors)    -   myopathies and lipid myopathies (such as carnitine        palmitoyltransferase I or II deficiency)

The preparation of some examples is described in detail below; the othercompounds of the formula I were obtained analogously:

EXPERIMENTAL SECTION Example 1

Synthesis of Compound 3:

10.0 g (17.9 mmol) of bromide 1 (WO 2005121161) are dissolved in 100 mlof dimethylformamide. Addition of 2.2 g of sodium azide is followed bystirring at room temperature for one hour. The reaction solution isextracted with water and ethyl acetate, and the organic phase is washedtwice more with saturated sodium chloride solution, filtered through alittle silica gel and concentrated. 11.3 g of crude product 2 areobtained. This azide 2 is dissolved in 300 ml of ethyl acetate and 1.5ml of triethylamine. Addition of 1 g of 10% palladium on activatedcarbon is followed by hydrogenation under a hydrogen pressure of 4 barfor 1 hour. The catalyst is removed on a little silica gel, and thesilica gel is washed with ethyl acetate. The solution is concentratedand the residue is purified by flash chromatography. 7.0 g of colorlesssolid 3 (80% yield over 2 stages) are obtained. TLC (ethyl acetate).R_(f)=0.3. C₂₇H₂₄NO₇ (493.49). MS (M+H)⁺=494.27.

Synthesis of Compound 4:

2.0 g (4.1 mmol) of amine derivative 3 are dissolved in 50 ml ofmethylene chloride. Addition of 30 ml of saturated aqueous sodiumbicarbonate solution is followed by cooling to 0° C. and addition of 2 g(6.7 mmol) of triphosgene (Aldrich). The reaction is allowed to takeplace at room temperature for 60 minutes. The solution is then washedwith saturated sodium bicarbonate solution, filtered through a littlesilica gel and concentrated, and 2.0 g of crude product isocyanate 4 areobtained as a colorless oil which is reacted further without furtherpurification (isocyanate 4 decomposes during chromatography).

Synthesis of Example 1

Synthesis of Compound 6:

940 mg (2.2 mmol) of anilide 5 (U.S. Pat. No. 5,994,391) and 940 mg (1.8mmol) of isocyanate 4 are dissolved in 50 ml of methylene chloride atroom temperature. After one hour at room temperature, the mixture isconcentrated to result in 1.9 g of crude product 6 as a colorless solid.TLC (n-heptane/ethyl acetate 1:1). R_(f)=0.3.

Synthesis of Example 1

1.9 g of crude product 6 are dissolved in 20 ml of methanol, and 0.5 mlof 1 M sodium methanolate/methanol solution is added. After 30 minutes,the reaction solution is neutralized with 1 ml of 0.5 M HCL/methanolsolution and concentrated. The residue is purified by flashchromatography. Yield 870 mg (76% over 2 stages) of Ex. 1 as colorlesssolid. TLC (methylene chloride/methanol/conc. ammonia 30/5/1).R_(f)=0.5. C₃₁H₄₄FN₃O₈S (637.77). MS (M+H)⁺=638.38.

Example 2

250.0 mg (0.39 mmol) of Example 1 are dissolved in 5 ml of pyridine and,after addition of 100 mg of pyridine-sulfur trioxide complex, stirred at60° C. for 30 minutes. Addition of 10 ml of methanol is followed byconcentration in a rotary evaporator. The residue is evaporated onceagain with 10 ml of methanol and then purified by flash chromatography.Yield 210 mg (75%) of Ex. 2 as ammonium salt. TLC (methylenechloride/methanol/conc. ammonia 30/5/1). R_(f)=0.3. C₃₁H₄₄FN₃O₁₁S₂×NH₃(734.87). MS (M+H)⁺=718.39

Synthesis of Isocyanate 9

Isocyanate 9 is prepared as crude product starting from bromide 7 (WO2004 052903) via the amine 8 in analogy to the synthesis of isocyanate4.

Example 3

Example 3 is prepared starting from 60 mg of isocyanate 9 and 184 mg ofaniline 5 in analogy to the synthesis of Example 1, and 50 mg (45% yieldover 2 stages) of Ex. 3 are obtained as a colorless solid. TLC(methylene chloride/methanol/conc. ammonia 30/5/1). R_(f)=0.5.C₃₁H₄₃F₂N₃O₈S (655.76). MS (M+H)⁺=656.32.

Example 4

Example 4 is prepared starting from 30 mg of Example 3 in analogy to thedescribed synthesis of Example 2, and 17 mg (55%) of ammonium salt ofExample 4 are obtained. TLC (methylene chloride/methanol/conc. ammonia30/5/1). R_(f)=0.3. C₃₁H₄₃F₂N₃O₁₁S₂×NH₃ (752.86). MS (M+H)⁻=734.39.

Example 5

Synthesis of Tosylate 10:

670 mg (1.1 mmol) of Example 1 are dissolved in 5 ml of pyridine and, atroom temperature, 460 mg (2.4 mmol) of p-tosly chloride are added. After1 hour at room temperature, 20 ml of methanol are added, and the solventis distilled off. The residue is purified by flash chromatography. Yield800 mg (96%) of tosylate 10 as colorless solid. TLC (methylenechloride/methanol/conc. ammonia 30/5/1). R_(f)=0.7. C₃₈H₅₀FN₃O₁₀S₂(791.97). MS (M+H)⁺=792.34.

Synthesis of Compound 11:

800 mg (1.0 mmol) of tosylate 10 are dissolved in 15 ml of pyridine and,at 0° C., 0.32 ml of benzoyl chloride is added. The cooling is removedand, after 1 hour at room temperature, 20 ml of methanol are added andthe solvent is distilled off. The residue is purified by flashchromatography. Yield 800 mg (80%) of compound 11 as colorless solid.TLC (n-heptane/ethyl acetate ½). R_(f)=0.5. C₅₂H₅₈FN₃O₁₂S₂ (1000.18). MS(M+H)⁺=1000.32.

Synthesis of Compound 12:

800 mg (0.8 mmol) of tosylate 11 are dissolved in 10 ml ofdimethylformamide. Addition of 550 mg of potassium thioacetate isfollowed by stirring at room temperature for 2 hours. The reactionsolution is extracted with water and ethyl acetate, and the organicphase is washed twice more with saturated sodium chloride solution,filtered through a little silica gel and concentrated. The residue ispurified by flash chromatography (n-heptane/ethyl acetate), and 560 mg(77% yield) of thioacetate 12 are obtained as a colorless solid. TLC(n-heptane/ethyl acetate 1:2). R_(f)=0.5. C₄₇H₅₄FN₃O₁₀S₂ (904.09). MS(M+H)⁺=904.29.

Synthesis of Compound 13:

Preparation of the Oxidizing Solution A:

-   1.5 ml of 30% strength aqueous hydrogen peroxide solution are    dissolved in 13.5 ml of formic acid and left to stand for 1 hour.    This solution can be stored in a refrigerator for several weeks.-   560 mg (0.62 mmol) of thioacetate 12 are dissolved in 14.5 ml of    oxidizing solution A. After 2 hours at room temperature, the mixture    is diluted with ethyl acetate and saturated sodium chloride    solution. The aqueous phase is extracted twice more with ethyl    acetate, and the collected organic phases are dried over magnesium    sulfate, filtered and concentrated. The residue is purified by flash    chromatography. Yield 446 mg (78%) of sulfonate 13 as yellowish    ammonium salt. TLC (methylene chloride/methanol/conc. ammonia    30/5/1). R_(f)=0.5. C₄₅H₅₂FN₃O₁₃S₂×NH₃ (943.09). MS (M+H)⁺=926.23.    Synthesis of Compound 14:

446 mg (0.47 mmol) of ammonium salt 13 are dissolved in 5 ml ofmethanol, and 0.5 ml of 1 M sodium methanolate/methanol solution isadded. After 30 minutes, the reaction solution is neutralized with 1 mlof 0.5 M HCL/methanol solution and concentrated. The residue is purifiedby flash chromatography. Yield 293 mg (84%) of N-oxide 14 as colorlesssolid. TLC (methylene chloride/methanol/conc. ammonia 30/15/5).R_(f)=0.2. C₃₁H₄₄FN₃O₁₁S₂×NH₃(734.87). MS (M+H)⁺=718.24.

Example 5

287 mg (0.39 mmol) of N-oxide 14 are dissolved in 10 ml of methanol and2 ml of 0.5 M HCl/methanol. Addition of 200 mg of 10% palladium onactivated carbon is followed by hydrogenation under a hydrogen pressureof 6 bar for 1 hour. The solution is concentrated and the residue ispurified by flash chromatography. Yield 205 mg (73%) of sulfonate ofExample 5 as colorless solid. TLC (methylene chloride/methanol/conc.ammonia 30/15/5). R_(f)=0.6. C₃₁H₄₄FN₃O₁₀S₂×NH₃(718.87). MS(M+H)⁺=702.19.

1. A compound of the formula I

wherein X is O, NH, CH₂ or a bond; R1 is (C₁-C₆)-alkyl; R2, R2′, R3,R3′, R4, R4′, R5, R5′ are, independently of one another, H, F, Cl, Br,I, OH, —(CH₂)—OH, CH₂F, CHF₂, CF₃, NO₂, N₃, CN, S(O)_(p)—R6,(C₁-C₆)-alkylene-S(O)_(p)—R6, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more than one, or allhydrogen(s) in the alkyl radicals may be replaced by fluorine; phenyl,—(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl, O—(CH₂)_(m)-phenyl,—(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl ring may be substituted oneto 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH,COO—(C₁-C₆)-alkyl or CONH₂; wherein at least one of the radicals R2,R2′, R3, R3′, R4, R4′ has the meaning of fluorine or R5, R5′ has themeaning of CH₂F, CHF₂ or CF₃; R6 is H, OH, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl or N((C₁-C₆)-alkyl)₂; n is 2, 3, 4, 5 or 6; m is 1, 2,3, 4, 5 or 6; p is 0, 1 or 2; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 wherein X is NH; R1 is(C₁-C₆)-alkyl; R2, R2′, R3, R3′, R4, R4′, R5, R5′ are, independently ofone another, H, F, Cl, Br, I, OH, —(CH₂)—OH, CH₂F, CHF₂, CF₃, NO₂, N₃,CN, S(O)_(p)—R6, (C₁-C₆)-alkylene-S(O)_(p)—R6, COOH, COO(C₁-C₆)alkyl,CONH₂, CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more thanone, or all hydrogen(s) in the alkyl radicals may be replaced byfluorine; phenyl, —(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl,O—(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl ring may be substituted oneto 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN,OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH,COO—(C₁-C₆)-alkyl or CONH₂; wherein at least one of the radicals R2,R2′, R3, R3′, R4, R4′ has the meaning of fluorine or R5, R5′ has themeaning of CH₂F, CHF₂ or CF₃; R6 is H, OH, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl or N((C₁-C₆)-alkyl)₂; n is 2, 3, 4, 5 or 6; m is 1, 2,3, 4, 5 or 6; p is 0, 1 or 2; or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 2 wherein X is NH; R1 is(C₁-C₆)-alkyl; R4 is F; R4′ is H or F; R2, R2′, R3, R3′, R5, R5′ are,independently of one another, H, F, Cl, Br, I, OH, —(CH₂)—OH, CH₂F,CHF₂, CF₃, NO₂, N₃, CN, S(O)_(p)—R6,(C₁-C₆)-alkylene-S(O)_(p)—R6, COOH,COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, whereone, more than one, or all hydrogen(s) in the alkyl radicals may bereplaced by fluorine; phenyl, —(CH₂)-phenyl, —(CH₂)_(n)-phenyl,O-phenyl, O—(CH₂)_(m)-phenyl, —(CH₂)—O—(CH₂)_(m)-phenyl, where thephenyl ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF₃,NO₂, CN,OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂; R6 is H,OH, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl or N((C₁-C₆)-alkyl)₂; n is 2, 3,4, 5 or 6; m is 1, 2, 3, 4, 5 or 6; p is 0, 1 or 2; or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1wherein X is O, NH, CH₂ or a bond; R1 is (C₁-C₆)-alkyl; R2, R2′, R3,R3′, R4, R4′ are, independently of one another, H, F, Cl, Br, I, OH,—(CH₂)—OH, CH₂F, CHF₂, CF₃, NO₂, N₃, CN,S(O)_(p)—R6,(C₁-C₆)-alkylene-S(O)_(p)—R₆, COOH, COO(C₁-C₆)alkyl,CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more thanone, or all hydrogen(s) in the alkyl radicals may be replaced byfluorine; phenyl, —(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl,O—(CH₂)_(m)-phenyl, —(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl ring maybe substituted one to 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN,OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂; R5, R5′ are, independently ofone another, H, —(CH₂)—OH, CH₂F, CHF₂,CF₃, S(O)_(p)—R6,(C₁-C₆)-alkylene-S(O)_(p)—R6,COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl], (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more than one, or allhydrogen(s) in the alkyl radicals may be replaced by fluorine; phenyl,—(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl, O—(CH₂)_(m)-phenyl,—(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl ring may be substituted oneto 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH,COO—(C₁-C₆)-alkyl or CONH₂; wherein at least one of the radicals R2,R2′, R3, R3′, R4, R4′ has the meaning of fluorine or R5, R5′ has themeaning of CH₂F, CHF₂ or CF₃; R6 is H, OH, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl or N((C₁-c₆)-alkyl)₂; n is 2, 3, 4, 5 or 6; m is 1, 2,3, 4, 5 or 6; p is 0, 1 or 2; or a pharmaceutically acceptable saltthereof.
 5. The compound of claim 4 wherein X is NH; R1 is(C₁-C₆)-alkyl; R2, R2′, R3, R3′, R4, R4′ are, independently of oneanother, H, F, Cl, Br, I, OH, —(CH₂)—OH, CH₂F, CHF₂, CF₃, NO₂, N₃, CN,S(O)_(p)—R6, (C₁-C₆)-alkylene-S(O)_(p)—R6, COOH, COO(C₁-C₆)alkyl,CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆) -alkyl,(C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more thanone, or all hydrogen(s) in the alkyl radicals may be replaced byfluorine; phenyl, —(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl,O—(CH₂)_(m)-phenyl, —(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl ring maybe substituted one to 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN,OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂; R5, R5′ are, independently ofone another, H, —(CH₂)—OH, CH₂CH₂F, CHF₂, CF₃, S(O)_(p)—R6,(C₁-C₆)-alkylene-S(O)_(p)—R6, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more than one, or allhydrogen(s) in the alkyl radicals may be replaced by fluorine; phenyl,—(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl, O—(CH₂)_(m)-phenyl,—(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl ring may be substituted oneto 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH,COO—(C₁-C₆)-alkyl or CONH₂; wherein at least one of the radicals R2,R2′, R3, R3′, R4, R4′ has the meaning of fluorine or R5, R5′ has themeaning of CH₂F, CHF₂ or CF₃; R6 is H, OH, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl or N((C₁-C₆)-alkyl)₂; n is 2, 3, 4, 5 or 6; m is 1, 2,3, 4, 5 or 6; p is 0, 1 or 2; or a pharmaceutically acceptable saltthereof.
 6. The compound of claim 5 wherein X is NH; R1 is(C₁-C₆)-alkyl; R4 is F; R4′ is H or F; R2, R2′, R3, R3′ are,independently of one another, H, F, Cl, Br, I, OH, —(CH₂)—OH, CH₂F,CHF₂, CF₃, NO₂, N₃, CN, S(O)_(p)—R6, (C₁-C₆)-alkylene-S(O)_(p)—R6, COON,COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, whereone, more than one, or all hydrogen(s) in the alkyl radicals may bereplaced by fluorine; phenyl, —(CH₂)-phenyl, —(CH₂)_(n)-phenyl,O-phenyl, O—(CH₂)_(m)-phenyl, —(CH₂)—O—(CH₂)_(m)-phenyl, where thephenyl ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂; R5, R5′are, independently of one another, H, —(CH₂)—OH, CH₂F, CHF₂, CF₃,S(O)_(p)—R6, (C₁-C₆)-alkylene-S(O)_(p)—R6, COOH, COO(C₁-C₆)alkyl, CONH₂,CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, where one, more than one, or allhydrogen(s) in the alkyl radicals may be replaced by fluorine; phenyl,—(CH₂)-phenyl, —(CH₂)_(n)-phenyl, O-phenyl, O—(CH₂)_(m)-phenyl,—(CH₂)—O—(CH₂)_(m)-phenyl, where the phenyl ring may be substituted oneto 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH,COO—(C₁-C₆)-alkyl or CONH₂; R6 is H, OH, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl or N((C₁-C₆)-alkyl)₂; n is 2, 3, 4, 5 or 6; m is 1, 2,3, 4, 5 or 6; p is 0, 1 or 2; or a pharmaceutically acceptable saltthereof.
 7. The compound of claim 6 wherein X is NH; R1 is(C₁-C₆)-alkyl; R4 is F; R4′ is H or F; R2, R3 is OH; R2′, R3′ is H; R5is —(CH₂)—OH, CH₂F, CHF₂, CF₃, S(O)_(p)—R6(C₁-C₆)-alkylene-S(O)_(p)—R6,COOH, COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, whereone, more than one, or all hydrogen(s) in the alkyl radicals may bereplaced by fluorine; R5′ is H; R6 is H, OH, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl or N((C₁-C₆)-alkyl)₂; n is 2, 3, 4, 5 or 6; m is 1, 2,3, 4, 5 or 6; p is 0, 1 or 2; or a pharmaceutically acceptable saltthereof.
 8. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof of claim
 1. 9. Thepharmaceutical composition of claim 8 comprising at least one furtheractive ingredient.
 10. The pharmaceutical composition of claim 9 whereinsaid further active ingredient is a compound which normalizes lipidmetabolism.
 11. The pharmaceutical composition of claim 9 wherein saidfurther active ingredient is selected from the group consisting ofantidiabetics, hypoglycemic active ingredients, HMGCoA reductaseinhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPARalpha agonists, PPAR alpha/gamma agonists, PPAR delta agonists,fibrates, MTP inhibitors, bile acid absorption inhibitors, MTPinhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDLreceptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipaseinhibitors, ATP-citrate lyase inhibitors, squalene synthetaseinhibitors, lipoprotein(a) antagonists, HM74A receptor agonists, lipaseinhibitors, insulins, sulfonylureas, biguanides, meglitinides,thiazolidinediones, α-glucosidase inhibitors, active ingredients whichact on the ATP-dependent potassium channel of the beta cells, glycogenphosphorylase inhibitors, glucagon receptor antagonists, activators ofglucokinase, inhibitors of gluconeogenesis, inhibitors offructose-1,6-bisphosphatase, modulators of glucose transporter 4,inhibitors of glutamine-fructose-6-phosphate amidotransferase,inhibitors of dipeptidylpeptidase IV, inhibitors of11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosinephosphatase 1B, modulators of the sodium-dependent glucose transporter 1or 2, modulators of GPR40, inhibitors of hormone-sensitive lipase,inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvatecarboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitorsof protein kinase C beta, endothelin-A receptor antagonists, inhibitorsof I kappaB kinase, modulators of the glucocorticoid receptor, CARTagonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNFagonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3agonists, CB1 receptor antagonists, MSH (melanocyte-stimulating hormone)agonists, CCK agonists, serotonin reuptake inhibitors, mixedserotoninergic and noradrenergic compounds, 5HT agonists, bombesinagonists, galanin antagonists, growth hormones, growth hormone-releasingcompounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptinagonists, DA agonists (bromocriptine, Doprexin), lipase/amylaseinhibitors, PPAR modulators, RXR modulators or TR-β agonists oramphetamines.
 12. The pharmaceutical composition of claim 8 whichcomprises as further excipient one or more metal salts.
 13. A method oftreating lipid metabolism disorders comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt thereof.
 14. A methodof treating hyperlipidemia comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 15. A method of lowering theserum cholesterol level comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 16. A method of treatingarteriosclerotic manifestations comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of claim 1or a pharmaceutically acceptable salt thereof.
 17. A method of treatinginsulin resistance comprising administering to a patient in need thereofa therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 18. A method of treatingdiabetes comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.